Method of making 2,4-dialkylquinolines and of decomposing amineketone reaction products



Patented Oct. 5, 1937 g UNITED STATES PATENT OFFICE- METHOD OF MAKING 2,4-DIALKYLQUIN- OLINES AND OF DECOMPOSING AMINE- KETONE REACTION PRODUCTS David Craig, Silver Lake, Ohio, assignor to The B. F. Goodrich Company, New York, N. Y., a corporation of New York No Drawing. Application August 11, 1936, Serial No. 95,432

8 Claims. (Cl. 26038) This invention relates to an improved method the reaction product of acetone and aniline by for making substituted quinolines, particularly the process of this invention can be explained those in which there are hydrocarbon radicals on a logical basis if we accept the view of Redas substituent groupings in the 2- and 4-posidelein and later Workers, that the material called.

5 tions. Hitherto these materials have been eX- acetone anil is actually 2,2,4-trimethyl-L2- 5 pensive and troublesome to prepare in the pure dihydroquinoline (Ben, 65, 1511 (1932); J. Chem. state even by the method disclosed some years 8.00., 1327 (1933); Ben, 66, 59 (1933); J. Am. ago in German Patents 363,582 and 363,583 (May Chem. 800., 55, 2805 (1933)). Although the 22, 1922; Frdl., IV, 520) in which reaction prodmechanism of the reaction is not entirely clear n s of aliphatic ketones With p y a yl the formation of the dihydroquinoline from ace- 10 amines are py y at a r l iv ly h h mtone and aniline can be represented by Equa perature or heated with hydrogen chloride at a {71 11 I. lower temperature. This process was developed further by Clarke and Taylor, U. S. Patent I 15 1,701,144, Feb. 5, 1929. That older methods for CH3 15 the preparation of 2,4-dimethylquinoline have H C-CH; not been satisfactory is shown by the fact that I 21110 as late as 1935 a tedious and costly method was H CH3 C-H published for its preparation from 2-hydroxy- H pentanone-4 and aniline (see Bull. Soc. Chim. 1 H I 20 By contrast, the method described herein is o=o H economical Whether operated on the large or small scale and is Very easily carried out. Brief- 1y, it consists in heating a dihydroquinoline, such reaction of th1s Compound wlth metal 5 2,214 trimethy1 1,2 dihydroquinoline (or amide such as sodamide then can be represented even crude reaction products containing substiy Equations and The sodmm denva' tuted dihydroquinoline compounds and prepared W 1S apparfmtly re%enemted by the mecha from primary aromatic amines and aldehydes or nlsm 111115131" 1n q i IV Wlth F formalketone in the pre ence of an N meta1 ubsti... tion Of 2,4-(11methylqu1nol1ne and. 1S then'free t t d mid as a catalyst, The cataly t may be to repeat the cycle until substantially all of the 30 the metal amide derived from th quinoline acetone-aniline reaction product (A) is conpound undergoing treatment, or may be another verted.

Na N on; 35

NaNHg L CH: CH H 40 I CH3 CH: (13) amide capable of giving up the metal to the T Na quinoline compound under the conditions of the N CH3 N 45 reaction. The catalyst brings about a reduction \C=OH2 in the chemical saturation of the quinoline com- I pound, usually by the elimination of hydrogen CH CH3 OH or or a hydrocarbon of the paraffin or olefinic series and the formation of a double bond joining 50 the nitrogen and the adjacent carbon atom. CH3 CH3 The formation of 2,4-dimethylquinoline from (O) H V r Na 1; r l I Wm. fix s e p i e \IC/ (or 115? ob) CH3 (B) CH3 Y The exact chemicalstructure of many of the reaction products of primary aromatic amines" with carbonyl compounds, such as aldehydes or ketones, i'sinot known; It is known that there is 15 a strong tendency to 'form'products having the empirical composition of substituted dihydro- ,quinolines, the number and character oi'the'sub- A withcarbonyl compounds contain large or even 7 j stituents depending onthe particulan'aldehyde or ketoneor mixture thereof which is employed in" "each case. The lowest aldehyde, formaldehyde, is anexception and does not by'itself form quincline compounds. 'Ihereaction which gives rise to the substituted 'dihydroquinolines requires two molecules of the simple saturated j aldehydes or "j ketoneswforr each" moleculepf primary aromatic 3 amine, but the two may be combined in advance ltoiorm aldols" or their-dehydration: products. 7

which-function as theequivalents'of the simple aldehydes or ketones, Thus one mole of aniline reacts with two of acetaldehyde' or withcne of acetaldol or with oneof crotonaldehyde to form. a product empirically: V

"Further, diacetone alcohol or mesityl oxide may be considered as equivalents for acetone in the When such polymeric compounds are treated by the. process of this invention the dihydroquinoline nucleus is apparently converted to a quinoline .Any' of the dihydroquinoline compounds 'de-- scribedabova-whether in a pure state or as more J or less crude reaction products, may be converted to corresponding quinoline compounds by heating in the presence of an N-metal substituted amide. If the amide used as a catalyst is to; be formed from the quinoline compound itself, it maybe formed either by adding the free metal, prefer-' 5" V ably together with a trace of copper compound or othermaterial which facilitates the formation of metal amides, or by adding a suitable come pound of the metal capable of reaction'with the quinoline compound, such as a metal hydride. If the amide is formed from some other nitrogeneous base, it may be formed separatelyand ,added. either alone orin' solution in a suitable 'solvent.,. 'Examples of suitable catalysts 'sodamide, sodium anilide, potassiuin amide, mag-'1 nesium anilide, magnesium nitride, aluminum anilide, iodo magnesium anilide and calcium amide. It is believed that these metal amides I function as carriers of the metal'and give it up to the quinoline compounds before or duringthe 4O As a specific example of one embodiment of thei invention 2,2};-trimethyldihydroquinoline is prereaction involved in this invention.

pared, by the reaction of acetonewith aniline N-H no-o .1 7 CH3 I 7 o j 211,0

cnl y 110-11. o-H

and ketones react. with amines. i

In somecases' these dihydroquinoline-containing reaction products of primary aromatic'amines r 'preponderant proportions of polymeric. compounds. For example, .whenanilineis'reacted with acetaldehyde, a dimer can be formedjwhich is believed to 'haye the formular V v vacuo.

a; JfAm. chem. Soc., 55, 2806 (1933),). For

example, a mixture 0191650 g. (50 moles) of aniline and 127 cc. of concentrated hydrochloric acid (1.5 moles I-ICl) is placed in a 12-liter flask and maintained at 110 C. Atotal of 17,000 g. of ace: tone is allowed to flow through the mixture over a period of 5 hours. 'The vapors issuing from the reacting mixture are condensed and distilled.

The acetone thus recovered is returned as part f V of the 17,000 g. Aniline present in the cone: densate readilyseparates from the water and is als'o'returned to the reaction flask.

V Thereaction .mixture is neutralized byboil- "ing withan aqueous solution of g. of soda ash.

The oil is separated and fractionally distilled in,

Aniline (boiling up to 110, at 15 mm.) is The residue in the flask recovered 'for reuse.

weighs about 350 g. and consists of 68% of the.

monomeric 2,2,4-trimethyldihydroquinoline and 31% of the polymeric material. These latter materials are separated'bycontinuing the vacuum fractionation. The pure monomer boils at 116 C. at a pressure of 5 mm. of mercury and has a setting point of 25 C. The polymers are separated into a fraction boiling at 220 to 240 C. at 2 mm. (probably a dimer) and a small amount of a non-volatile brittle resin.

346 g. (2 moles) of the 2,2,4-trimethyldihydroquinoline is refluxed at 220-230 C. with a freshly prepared solution of 4.6 g. (0.2 mole) sodium in 56 g. (0.6 mole) of aniline. At the beginning, methane is evolved but at the end of 5 hours the evolution is completed. The mixture is cooled and washed with water if desired. In most cases with such small amounts of alkali it is not necessary to wash with water". The product, after the major part of the aniline has been distilled off along with a small amount of the 2.4-dimethylquinoline, is found to boil at approximately 90 C. at a pressure of 1 mm. The yield is about 261 g. The 2,4-dimethylquinoline is sufficiently pure for many purposes. It may be further purified by dissolving in dilute hydrochloric acid and extracting the solution with benzene to remove small amounts of weak bases such as diphenylamine, and then adding a strong solution of zinc chloride which precipitates the dimethylquinoline as a nearly insoluble zinci hydrochloride (British Patent 276,156; Chem. Zentr., 1928, II, 2287). After cooling, this is filtered off, washed with a little water and finally decomposed with a mixture of sodium hydroxide and sodium cyanide to yield the free base. If the product is then distilled, it is obtained colorless in a yield of about 209 g. or 68%. Similar results are obtained by substituting magnesium anilide for the sodium anilide.

As a further example, 50 g. of the brittle resinous polymeric dihydroquinoline from the above described acetone aniline reaction, distilling at 220240 at 2 mm., is heated to 350 C. with 0.5 g. of sodamide. A combustible gas is evolved vigorously. After minutes the temperature is raised to 410 for a few minutes. The main product distils at approximately 215-225 at 2.5 mm. (yield 33 g.). It gives analytical results satisfactory for a compound having the empirical formula of CzsHzeNz as shown by the following table:

Percentage Calcd. for

found C23H26N2 The volume of gas evolved during the reaction is approximately half the Volume evolved when an equal weight of the dihydroquinoline is used as in the first example. Inasmuch as 2,2,4-trimethyll,2,3,4-tetrahydroquinoline prepared by reduction of the dihydroquinoline does not evolve as gas when refluxed with its sodium derivative, it is believed that the reaction involves only the dihydroquinoline nucleus, as indicated in Equation VI:

uct of p-phenetidine and acetone of B. P. 130- 140 at 3 mm. is heated to reflux with 0.25 g. of sodamide for 2.5 hours. A, combustible gas is evolved during this time. The main product is B-ethoxy 2,4-dimethylquinoline which may be purified by distillation and crystallization from hexane. It melts at 85-86.

It is to be understood that the scope of the invention is not limited by the examples given, and many variations of it will be apparent to those skilled in the art. Instead of the amineketone reaction products mentioned, other dihydroquinolines prepared from primary aromatic amines such as an'amino hydrocarbon substituted benzene or a naphthylamine or an amino diaryl ether and a ketone such as methyl ethyl ketone, diethyl-ketone, methyl propyl ketone, mesityl oxide, methyl vinyl ketone and the like or the various aldehydes or mixtures of aldehydes and ketones can be used. It is accordingly to be understood that it is not intended to limit the scope of the invention except as may be required by the prior art and. as indicated in the appended. claims.

I claim:

1. The method of producing 2,4-dimethylquinoline which comprises heating 2,2,4-trimethyl dihydroquinoline with an amide of a light metal.

2. The method of producing a 2,4-substituted quinoline which comprises heating a substituted dihydroquinoline-containing reaction product of a primary aromatic amine and an aliphatic ketone with an amide of a light metal.

3. The method of preparing a substituted quinoline which comprises heating a 2-a1kyl-substituted dihydroquinoline with a metallic amide.

4. The method of preparing 2,4-dimethylquinoline which comprises heating 2,2,4-trimethyldihydroquinoline with sodium anilide.

5. The method of preparing a 2,4-substituted quinoline which comprises heating a substituted dihydroquinoline-containing aliphatic ketonearomatic amine reaction product with a magnesium amide.

6. The method of preparing 2,4-dimethyl-6- ethoxyquinoline which comprises heating a substituted dihydroquinolinecontaining p-phenetidine-acetone reaction product with sodium anilide.

7. The method of preparing a substituted quinoline which comprises heating a substituted dihydroquinoline-containing reaction product of a primary aromatic amine and at least one member containing more than one carbon atom of the group consisting of aliphatic aldehydes and ketones with a metallic amide.

8. The method of preparing a quinoline which comprises heating a reaction product of a primary aromatic amine with at least one member containing more than one carbon atom of the group consisting of aliphatic aldehydes and ketones, such product containing a dihydroquinoline and an alkali metal dissolved therein.

v1. 1 1 lTIa lTla N OH OH N N CH3 N (3-0253 0 o-om o i/ l m l i/ CH4 C ilHzsNzNa C 2a N2N As a third example, 45 g. of the reaction prod- DAVID CRAIG. 

